Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the oldest known human maladies. Yet this disease is still one of the major causes of mortality worldwide, killing 1.5 million people each year. Despite the widespread use of an attenuated live vaccine and several antibiotics, there is currently more TB than ever before. This dire situation is compounded by increasing prevalence of antibiotic-resistant Mtb whose emergence is facilitated by the lengthy course of antibiotic treatment and the ability of Mtb to persist in the host by counteracting the host immune defense mechanisms. Thus, new vaccines and drugs are required to achieve rapid elimination of Mtb from the human host. Mtb is a facultative intracellular pathogen that replicates within macrophages and extracellularly in lung cavities. During infection, M. tuberculosis must adapt to essential micronutrient limitation imposed by the host as part of an antimicrobial strategy known as nutritional immunity. In particular, the host scavenges essential metal ions, including iron (Fe) manganese (Mn) and zinc (Zn), to prevent their acquisition by the microbe. To counteract this limitation, Mtb possesses sophisticated molecular systems for sensing and acquisition of essential metals. Mn sequestration has recently emerged as an important mechanism of host resistance in several bacterial and fungal infections. Furthermore, inactivation of Mn homeostatic mechanisms has been shown to compromise the ability of many bacterial species to successfully colonize and cause disease within multiple hosts. However, the relevance of Mn to Mtb pathogenesis has not been investigated because the knowledge of the molecular mechanisms involved in Mtb Mn metabolism has been very limited. We recently identified two Mn transporters in Mtb, MntH and MntABCD, which are required to survive Mn limitation and replicate in human macrophages. We hypothesize that these transporters promote Mtb virulence by counteracting the activity of human Mn sequestration systems, the Nramp1 Mn transporter and Mn-binding protein calprotectin. This proposal will test this hypothesis by analyzing the functional interactions between host and pathogen Mn transport systems at the macrophage level and in the mouse model of TB. Using bacterial mutants lacking Mn transporters and macrophages and mice deficient in Nramp1 and calprotectin, we will characterize the contribution of Mn import to Mtb pathogenesis. This study has the potential to guide the development of novel pathogen and/or host directed therapies designed to harness the host defense mechanism of Mn starvation.